Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents

Ren, Junyu; Agata, Naoki; Chen, Dongshu; Li, Yongqing; Yu, Winston; Huang, Lei; Raina, Deepak; Chen, Wen; Kharbanda, Surender; Küfe, Donald

doi:10.1016/s1535-6108(04)00020-0

Cited by 308 publications

(432 citation statements)

References 48 publications

Supporting

Mentioning

411

Contrasting

Unclassified

Order By: Relevance

“…In this regard, MUC1 signaling is activated by cytokines in myeloma cells (19) and by ErbB receptors in carcinoma cells (21,25). In HCT116 carcinoma cells, enforced expression of MUC1 has no detectable effect on the PI3K/Akt or Bcl-x L pathways (50). Moreover, in carcinoma cells, localization of MUC1 C-ter to mitochondria is associated with attenuation of the apoptotic response to diverse types of stress (50,51).…”

Section: Muc1mentioning

confidence: 99%

“…In HCT116 carcinoma cells, enforced expression of MUC1 has no detectable effect on the PI3K/Akt or Bcl-x L pathways (50). Moreover, in carcinoma cells, localization of MUC1 C-ter to mitochondria is associated with attenuation of the apoptotic response to diverse types of stress (50,51). Thus, MUC1 can block apoptosis by different mechanisms that are dependent on cell context.…”

Section: Muc1mentioning

confidence: 99%

See 1 more Smart Citation

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

Self Cite

152

143

View full text Add to dashboard Cite

The MUC1 transmembrane glycoprotein is overexpressed by most human carcinomas. Overexpression of MUC1 confers transformation; however, the signaling pathways activated by this oncoprotein are largely unknown. The present studies demonstrated that MUC1-induced transformation of 3Y1 fibroblasts is associated with increased levels of phospho-Akt and phospho-Bad. The finding that LY294002 blocks MUC1-mediated increases in phospho-Akt and phospho-Bad supports the involvement of phosphoinositide 3-kinase (PI3K) as an upstream effector of this response. We also show that MUC1 increases the expression of the anti-apoptotic Bcl-x L protein (but not Bcl-2) by a PI3K-independent mechanism. In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-␤-D-arabinofuranosylcytosine. Similar results were obtained with the anti-cancer agent, gemcitabine. These findings indicate that expression of MUC1 in 3Y1 cells activates the anti-apoptotic PI3K/Akt and Bcl-x L pathways.The phosphoinositide 3-kinase (PI3K) 1 /Akt signaling pathway is of importance in promoting cell survival. PI3K, which consists of a p85 regulatory subunit and a p110 catalytic subunit, phosphorylates phosphatidylinositols (PIs) at their 3-position and thereby converts PI(4,5)P 2 to PI(3,4,5)P 3 (1). The serine-threonine Akt/PKB kinase and the phosphoinositide-dependent kinase 1 (PDK1) localize at cell membrane sites by direct binding to PI(3,4,5)P 3 through their pleckstrin-homology domains (2, 3). Phosphorylation of Akt by PDK1 stimulates Akt activity (4). In turn, Akt phosphorylates and inactivates the Forkhead-related transcription factor 1 by retaining it in the cytosol in a complex with 14-3-3 proteins. Similarly, Akt phosphorylates Bad, induces binding of Bad to 14-3-3 proteins, and prevents Bad from interacting with the anti-apoptotic Bcl-2 and Bcl-x L proteins (5). The activity of the pro-death caspase-9 protease is inhibited by Akt-mediated phosphorylation (6). Akt can also confer cell survival by indirect regulation of NF-B through I B kinase (7, 8) and of p53 through Mdm2 (9, 10). These findings, and the demonstration that PI3K/Akt signaling is dysregulated in human malignancies, have provided support for the significance of this pathway in conferring tumor cell survival (11).The human DF3/MUC1 transmembrane glycoprotein is expressed on the apical borders of normal secretory epithelial cells (12). The MUC1 protein is synthesized as a single polypeptide that is cleaved in the endoplasmic reticulum into N-terminal and C-terminal subunits, which then reside as heterodimers at the apical cell surface (13,14). The large (Ͼ250 kDa) N-terminal ectodomain (N-ter) contains variable numbers of 20-amino acid tandem repeats that are heavily glycosylated (15, 16). The smaller (ϳ25 kDa) C-terminal subunit (C-ter) consists of an extracellular domain of 58 amino acids, a 28-amino acid transmembrane...

show abstract

Section: Muc1mentioning

confidence: 99%

Section: Muc1mentioning

confidence: 99%

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

Self Cite

152

143

View full text Add to dashboard Cite

show abstract

“…The >250-kDa MUC1-N ectodomain associates with the f25-kDa MUC1-C as a heterodimer or, in response to certain stimuli, is released from the cell surface (2). Importantly, overexpression of MUC1 confers transformation and blocks the apoptotic response to anticancer agents (8)(9)(10)(11)(12). MUC1 interacts with members of the ErbB family of receptor tyrosine kinases (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling

Ren

Raina²,

Chen³

et al. 2006

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

Activation of the fibroblast growth factor (FGF) receptor 3 (FGFR3) has been linked to the development of human cancers by mechanisms that are not well understood. The MUC1 oncoprotein is aberrantly overexpressed by certain hematologic malignancies and most human carcinomas. The present studies show that MUC1 associates with FGFR3. Stimulation of cells with FGF1 increased the interaction between MUC1 and FGFR3. FGF1 stimulation also induced c-Src-dependent tyrosine phosphorylation of the MUC1 cytoplasmic domain on a YEKV motif. FGF1-induced tyrosine phosphorylation of MUC1 was associated with increased binding of MUC1 to B-catenin and targeting of MUC1 and B-catenin to the nucleus. FGF1 also induced binding of MUC1 to the heat shock protein 90 (HSP90) chaperone by a mechanism dependent on phosphorylation of the YEKV motif. Notably, B-catenin and HSP90 compete for binding to the MUC1 cytoplasmic domain, indicating that MUC1 forms mutually exclusive complexes with these proteins. The results also show that inhibition of HSP90 with geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin attenuates FGF1-induced binding of MUC1 to HSP90 and targeting of MUC1 to the mitochondrial outer membrane. These findings indicate that FGF1 induces phosphorylation of MUC1 on YEKV and thereby activates two distinct pathways: (a) nuclear localization of MUC1 and B-catenin and (b) delivery of MUC1 to mitochondria by HSP90. (Mol Cancer Res 2006;4(11):873 -83)

show abstract

“…However, with transformation and loss of polarity, MUC1 is expressed at high levels over the entire surface and in the cytosol of carcinoma cells (5). Importantly, overexpression of MUC1 induces transformation (6) and resistance to stress-induced apoptosis (7)(8)(9)(10)(11)(12). The MUC1 N-terminal ectodomain (MUC1-N) contains variable numbers of highly glycosylated 20 amino acid tandem repeats (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…The MUC1 C-terminal subunit (MUC1-C) consists of a 58 amino acid extracellular domain, a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic tail (15). MUC1-C is targeted to the nucleus (6,10,(16)(17)(18) and mitochondria (8,19). In addition, MUC1-C stabilizes the Wnt effector, ß-catenin, through direct binding of the MUC1-C cytoplasmic domain (MUC1-CD) and the ß-catenin Arm repeats (20).…”

Section: Introductionmentioning

confidence: 99%

Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

Self Cite

View full text Add to dashboard Cite

Abstract. The mucin (MUC) family consists of secreted and membrane-bound forms. The transmembrane mucin 1 (MUC1) is a heterodimer that is aberrantly overexpressed by diverse human carcinomas and certain hematologic malignancies. The MUC1 N-terminal (MUC1-N) and C-terminal (MUC1-C) subunits are generated by autocleavage within a SEA domain. The MUC1 cytoplasmic domain (MUC1-CD) located downstream of the SEA domain is sufficient for the induction of anchorage-independent growth and tumorigenicity; however, no information is available regarding the origin of these transforming sequences. Previous work demonstrated that, except for the SEA domain, MUC1 has no sequence homology with other membrane-bound mucins. The present results demonstrate that MUC1-CD evolved from repeat regions in the MUC5B secreted mucin. We also show that MUC1 sequences upstream to the SEA domain emerged from MUC5B. These findings indicate that both the MUC1-N and MUC1-C subunits evolved from secreted gel-forming mucins and that the MUC1-CD oncogenic function emerged by diversification after evolution from MUC5B.

show abstract

Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents

Cited by 308 publications

References 48 publications

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling

Evolution of the human MUC1 oncoprotein

Contact Info

Product

Resources

About